Darell Bigner

Overview:

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I am Principal Investigator, is currently in its 27th year of continuous funding. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Positions:

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1965

Duke University

Ph.D. 1971

Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

Grants:

NCI Howard Temin Award (K01) Transition

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Anti-tumor efficacy of EGFR-targeting immunotoxin in combination with CCNU or PD-L1 blockade in glioma mouse models

Administered By
Neurosurgery, Neuro-Oncology
Role
Principal Investigator
Start Date
End Date

Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Oncolytic PVSRIPO Expressing Tumor Antigens as a Cancer Vaccine

Administered By
Neurosurgery
Role
Significant Contributor
Start Date
End Date

Oncolytic Poliovirus Immunotherapy of Malignant Glioma

Administered By
Pathology
Role
Principal Investigator
Start Date
End Date

Publications:

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

Authors
Desjardins, A; Gromeier, M; Herndon, JE; Randazzo, D; Threatt, S; Lipp, ES; Miller, ES; Jackman, J; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Peters, KB; Johnson, MO; Sampson, JH; Ashley, DM; Bigner, DD
MLA Citation
Desjardins, Annick, et al. “Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. 2060–2060. Crossref, doi:10.1200/jco.2019.37.15_suppl.2060.
URI
https://scholars.duke.edu/individual/pub1415615
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
2060
End Page
2060
DOI
10.1200/jco.2019.37.15_suppl.2060

BEVACIZUMAB, IRINOTECAN, TEMOZOLOMIDE, TYROSINE KINASE INHIBITION, AND MEK INHIBITION ARE EFFECTIVE AGAINST PLEOMORPHIC XANTHOASTROCYTOMA REGARDLESS OF V600E STATUS

Authors
MLA Citation
URI
https://scholars.duke.edu/individual/pub1375562
Source
wos
Published In
Neuro Oncology
Volume
20
Published Date
Start Page
102
End Page
102

Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status.

INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA. METHODS: The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5-10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6-9). Subcutaneous tumor growth and survival were the endpoints. RESULTS: Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001). CONCLUSIONS: These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.
Authors
MLA Citation
Thompson, Eric M., et al. “Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status..” J Neurooncol, vol. 140, no. 2, Nov. 2018, pp. 261–68. Pubmed, doi:10.1007/s11060-018-2975-5.
URI
https://scholars.duke.edu/individual/pub1344226
PMID
30120661
Source
pubmed
Published In
J Neurooncol
Volume
140
Published Date
Start Page
261
End Page
268
DOI
10.1007/s11060-018-2975-5

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma.

Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5-10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3γ, WNTα, and WNTβ (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.
Authors
Thompson, EM; Brown, M; Dobrikova, E; Ramaswamy, V; Taylor, MD; McLendon, R; Sanks, J; Chandramohan, V; Bigner, D; Gromeier, M
MLA Citation
Thompson, Eric M., et al. “Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma..” J Neuropathol Exp Neurol, vol. 77, no. 8, Aug. 2018, pp. 696–702. Pubmed, doi:10.1093/jnen/nly045.
URI
https://scholars.duke.edu/individual/pub1322157
PMID
29878245
Source
pubmed
Published In
J Neuropathol Exp Neurol
Volume
77
Published Date
Start Page
696
End Page
702
DOI
10.1093/jnen/nly045

The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma.

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.
Authors
Diplas, BH; He, X; Brosnan-Cashman, JA; Liu, H; Chen, LH; Wang, Z; Moure, CJ; Killela, PJ; Loriaux, DB; Lipp, ES; Greer, PK; Yang, R; Rizzo, AJ; Rodriguez, FJ; Friedman, AH; Friedman, HS; Wang, S; He, Y; McLendon, RE; Bigner, DD; Jiao, Y; Waitkus, MS; Meeker, AK; Yan, H
MLA Citation
Diplas, Bill H., et al. “The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma..” Nat Commun, vol. 9, no. 1, May 2018. Pubmed, doi:10.1038/s41467-018-04448-6.
URI
https://scholars.duke.edu/individual/pub1319362
PMID
29802247
Source
pubmed
Published In
Nature Communications
Volume
9
Published Date
Start Page
2087
DOI
10.1038/s41467-018-04448-6